Targeting VCX2 in Hepatocellular Carcinoma: An Omics-Guided Druggability Study Using Peruvian Natural Products

Abstract Hepatocellular carcinoma (HCC) is among the deadliest cancers, and current biomarkers offer limited diagnostic and therapeutic utility. To uncover novel druggable targets, we employed an omics-guided computational pipeline that combines single-cell RNA sequencing (scRNA-seq), differential gene expression (DGE) analysis, UMAP clustering, and protein–protein interaction (PPI) network mapping. Among the prioritized genes—TMBIM4, RGS5, CEACAM7, and VCX2—the cancer/testis antigen VCX2 stood out for its aberrant expression and potential role in chromosomal instability. The VCX2 structure was modeled via AlphaFold2 and refined to reveal druggable pockets for virtual screening using the PeruNPDB (Peruvian Natural Products Database). Docking identified luteolin-5-O-glucoside from Equisetum arvense as the top ligand (Docking score: − 7.42 kcal/mol; ΔGbind: − 40.13 ± 1.12 kcal/mol). MM-GBSA and interaction analysis showed stable hydrogen bonds with PRO91, GLU97, and GLU109. These findings highlight VCX2 as a promising target for HCC and suggest luteolin-5-O-glucoside as a potential lead scaffold. Further molecular dynamics and SAR studies are needed to validate and optimize its efficacy.